Protective variant for hippocampal atrophy identified by whole exome sequencing.
Nho K., Kim S., Risacher SL., Shen L., Corneveaux JJ., Swaminathan S., Lin H., Ramanan VK., Liu Y., Foroud TM., Inlow MH., Siniard AL., Reiman RA., Aisen PS., Petersen RC., Green RC., Jack CR., Weiner MW., Baldwin CT., Lunetta KL., Farrer LA., MIRAGE (Multi-Institutional Research on Alzheimer Genetic Epidemiology) Study None., Furney SJ., Lovestone S., Simmons A., Mecocci P., Vellas B., Tsolaki M., Kloszewska I., Soininen H., AddNeuroMed Consortium None., McDonald BC., Farlow MR., Ghetti B., Indiana Memory and Aging Study None., Huentelman MJ., Saykin AJ., Alzheimer's Disease Neuroimaging Initiative None.
We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.